23 research outputs found
Exploring the complementarity of pancreatic ductal adenocarcinoma preclinical models
Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental De-sign: Three paired PDAC preclinical modelsâpatientâderived xenografts (PDX), xenograftâderived pancreatic organoids (XDPO) and xenograftâderived primary cell cultures (XDPCC)âwere derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basalâlike/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5âfluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivityâassociated pathways and PDX and XDPCC for the chemoresistanceâassociated pathways. Conclusions: Each PDAC preclinical model possesses a unique basalâlike/classical transcriptomic phenotype that strongly in-fluences their global chemosensitivity. Each preclinical model is imperfect but complementary, sug-gesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applica-bility to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.Fil: Hoare, Owen. Centre National de la Recherche Scientifique; FranciaFil: Fraunhoffer Navarro, Nicolas Alejandro. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Centro de Estudios FarmacolĂłgicos y BotĂĄnicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios FarmacolĂłgicos y BotĂĄnicos; ArgentinaFil: Elkaoutari, Abdessamad. Centre National de la Recherche Scientifique; FranciaFil: Gayet, Odile. Centre National de la Recherche Scientifique; FranciaFil: Bigonnet, Martin. Centre National de la Recherche Scientifique; FranciaFil: Roques, Julie. Centre National de la Recherche Scientifique; FranciaFil: Nicolle, RĂ©my. No especifĂca;Fil: McGuckin, Colin. Cell Therapy Research Institute; FranciaFil: Forraz, Nico. Cell Therapy Research Institute; FranciaFil: Sohier, Emilie. Le Centre RĂ©gional de Lutte Contre Le Cancer LĂ©on BĂ©rard; FranciaFil: Tonon, Laurie. Le Centre RĂ©gional de Lutte Contre Le Cancer LĂ©on BĂ©rard; FranciaFil: Wajda, Pauline. Le Centre RĂ©gional de Lutte Contre Le Cancer LĂ©on BĂ©rard; FranciaFil: Boyault, Sandrine. Le Centre RĂ©gional de Lutte Contre Le Cancer LĂ©on BĂ©rard; FranciaFil: Attignon, ValĂ©ry. Le Centre RĂ©gional de Lutte Contre Le Cancer LĂ©on BĂ©rard; FranciaFil: Tabone, Luciana Belen. Le Centre RĂ©gional de Lutte Contre Le Cancer LĂ©on BĂ©rard; FranciaFil: Barbier, Sandrine. No especifĂca;Fil: Mignard, Caroline. No especifĂca;Fil: Duchamp, Olivier. No especifĂca;Fil: Iovanna, Juan. Centre National de la Recherche Scientifique; FranciaFil: Dusetti, Nelson J.. Centre National de la Recherche Scientifique; Franci
EZH2 alterations in follicular lymphoma: biological and clinical correlations
International audienceThe histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n = 55) and H3K27 methylation (n = 63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n = 46, gain n = 23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36â0.93, P = 0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies
Alterations in Homologous Recombination-Related Genes and Distinct Platinum Response in Metastatic Triple-Negative Breast Cancers: A Subgroup Analysis of the ProfiLER-01 Trial
International audienc
An injectable and porous hydrogel with potential as a support for functional skeletal muscle regeneration
International audienc
Innovative injectable and porous hydrogels as a support for striated skeletal muscle tissue engineering
International audienc
Innovative injectable and porous hydrogels as a support for striated skeletal muscle tissue engineering
International audienc
Versatile injectable and porous hydrogels: new perspectives for skeletal muscle tissue regeneration
International audienc
Versatile injectable and porous hydrogels: new perspectives for skeletal muscle tissue regeneration
International audienc
Versatile injectable and porous hydrogels: new perspectives for skeletal muscle tissue regeneration
International audienc
Design of injectable and porous hydrogels and their potential as support for skeletal muscle tissue engineering
International audienc